This invention relates to improvements in whitening compositions and methods of using same. In particular, the invention provides whitening compositions and methods that use free radicals of nitrogen oxide and/or nitric oxide and/or other nitroxyls to achieve a faster and improved level of whitening.
As a background on whitening generally, and more particularly on tooth whitening, it may first be noted that a tooth is comprised of an inner dentin layer and an outer hard enamel layer that is the protective layer of the tooth. The enamel layer of a tooth is naturally an opaque white or slightly off-white color. It is this enamel layer that can typically become stained or discolored. The enamel layer of a tooth is composed of hydroxyapatite mineral crystals that create a somewhat porous surface. It is believed that this porous nature of the enamel layer is what allows staining agents and discoloring substances to permeate the enamel and discolor the tooth.
Many substances that a person confronts or comes in contact with on a daily basis can “stain” or reduce the “whiteness” of one's teeth. In particular, the foods, tobacco products and fluids such as tea and coffee that one consumes tend to stain one's teeth. These products or substances tend to accumulate on the enamel layer of the tooth and form a pellicle film on the teeth. These staining and discoloring substances can then permeate the enamel layer. This problem occurs gradually over many years, but imparts a noticeable discoloration of the enamel of one's teeth.
There are available to dentists and consumers many different oral compositions for home and professional in-office use which contain 1-45% by weight concentrations of a peroxygen compound such as hydrogen peroxide which when applied on the teeth may effect whitening of stains. These compositions all require different amounts of time to achieve a tooth whitening effect. These times range from 90 to 120 minutes for a dentist applied, light-activated whitening system to two weeks or more of over night exposure for tray-delivered whitening products. Currently even the top selling brands of dentist-applied, chair-side tooth whitening systems require a minimum of three (3) twenty-minute applications and an overall minimum of ninety (90) minutes or more to complete when all manufacturers' instructions are followed.
Among the chemical strategies available for removing or destroying tooth stains, the most effective compositions contain an oxidizing agent, usually a peroxygen compound such as hydrogen peroxide, in order to attack the chromogen molecules in such a way as to render them colorless, water-soluble, or both. In one of the most popular approaches to whitening a patient's teeth, a dental professional will construct a custom-made tooth-whitening tray for the patient from an impression made of the patient's dentition and prescribe the use of an oxidizing gel to be dispensed into the tooth-whitening tray and worn intermittently over a period of time ranging from about 2 weeks to about 6 months, depending upon the severity of tooth staining. These oxidizing compositions, usually packaged in small plastic syringes, are dispensed directly by the patient, into the custom-made tooth-whitening tray, held in place in the mouth for contact times of greater than about 60 minutes, and sometimes as long as 8 to 12 hours. The slow rate of whitening is in large part the consequence of the very nature of formulations that are developed to maintain stability of the oxidizing composition.
Alternatively, there are oxidizing compositions (generally those with relatively high concentrations of oxidizers) which are applied directly to the tooth surface of a patient in a dental office setting under the supervision of a dentist or dental hygienist. Theoretically, such tooth whitening strategies have the advantage of yielding faster results and better overall patient satisfaction.
Oral compositions for whitening teeth have also been available containing peracetic acid dissolved or suspended in a vehicle. The peracetic acid may have been generated within a dentifrice vehicle by combining water, acetylsalicylic acid and a water soluble alkali metal percarbonate.
Formulations for oxygen liberating compositions for the whitening of teeth have also been used in either anhydrous or hydrated pastes or gels. Hydrated examples include an aqueous oral gel composition including about 0.5 to about 10% by weight urea peroxide and 0.01 to 2% by weight of a fluoride providing compound, and/or a water containing a hydrogen peroxide-Pluronic thickened oral gel composition.
Another example includes a toothpaste containing a combination of calcium peroxide and sodium perborate oxidizing agents, dicalcium phosphate, calcium carbonate and magnesium carbonate cleaning agents, sorbitol humectant, cornstarch and cellulose gum thickening agents, and an anionic detergent. Other examples include oral compositions containing peroxyacids and alkyl diperoxy acids having alkylene groups containing 5-11 carbon atoms for removing stains from teeth.
The prolonged period needed for effective whitening may be undesirably time-consuming. Thus, any whitening system that can potentially reduce the time factor is preferable. To accomplish this in the present invention, it has been recognized that nitrogen-containing free radicals and various related nitroxyl-based free radicals are more reactive than the oxygen singlet free radicals that are generated by all previously described tooth whitening compositions. The present invention then makes use of the release of free radicals containing nitrogen to effect a more rapid whitening of the teeth.
First, some background information on nitrogen oxide (NO) will be presented. NO is one of the oldest molecules on earth, being formed in the primitive atmosphere of the cooling planet. Until recently, NO had been regarded almost solely as a predominantly harmful product, being the cause of, for example, acid rain and atmospheric pollution. However in 1987, NO was discovered to be the chemical responsible for the actions of endothelial derived relaxing factor. Following this finding, NO research has expanded exponentially, and it is now regarded by many in the scientific community as one of the greatest discoveries of the 20th century. In recognition of this, two Nobel prizes have been awarded to researchers in the NO field, and it was named as molecule of the year by the scientific journal, Science, in 1998.
NO is a small gaseous molecule with chemical properties that make it uniquely suitable as both an intra- and inter-cellular messenger. Because it possesses an unpaired electron, NO reacts with other molecules with unpaired electrons, including colored organic molecules known as chromogens.
As a neutral gaseous molecule, NO can diffuse over several cell lengths from its source to exert control over certain enzymes and regulate key cellular functions. Also, because of its reactivity, NO has been used as an effector molecule to kill tumors and pathogens. The combined properties of its ability to regulate enzymes across long distances as well as its high, reactivity with other molecules give NO its unique dual role as both a powerful signaling molecule and lethal effector molecule.
Because of these powerful functions, the production of this pivotal mediator is tightly regulated and there is ample literature to show that too little or too much NO production contributes to numerous human diseases and disorders. Decreased NO generation in the penis, for example, results in impotence. Decreased NO generation is also thought to have a role in hypertension.
Nitric oxides are known to be as much as five or more times more reactive than oxygen free radicals. This is based on research that shows that oxyhemoglobin binds NO faster by five to six orders of magnitude than oxygen.
It is estimated the half-life of NO free radical is close to five seconds. Even though short, it is of quite sufficient length to allow diffusion between enamel rods and over the enamel surface as prior research has shown that in five seconds the NO radical can diffuse many human lung cell diameters and enable it to function as a transcellular messenger. Research has shown that NO may diffuse the entire length of a cell (˜0.11 m) within a millisecond. Therefore the rate of travel within biological systems can be calculated to be 1 mm per second. Human tooth enamel is 2-3 mm thick; hence the 5 second half-life if NO is more than sufficient time for the free radical to travel to the entire depth of an enamel rod.
Research interest of NO in dentistry has been relatively recent, and only a small minority of the 50,000 papers currently cited on NO have been concerned with the oral sciences, although dentistry's interest in NO is expanding rapidly. Of greatest interest has been the role of NO in the pathogenesis and prevention of periodontal disease and in the biology of oral cancer.
The chemistry of NO reveals that its arrangement of one atom of nitrogen and one of oxygen leaves an unpaired electron, which makes the molecule a highly reactive free radical. The result is a molecule with special properties which, as described below, make it a previously-unrecognized ideal tooth whitening agent.
One of the primary advantages of NO over the superoxide free radical (the predominant species liberated in tooth whitening preparations containing hydrogen peroxide), is that NO has a low propensity to react with itself at physiological temperatures to form a nitrogen gas bubble. Contrarily, superoxide free radicals do react with themselves at an efficiency of 99.99% combining to form an oxygen bubble, and thus cause its efficiency at removing the color from chromophoric stains on teeth to be very low. It is for this reason that in nature, the NO free radical is 10 to 100 times more efficient in whitening organic matter. As a result, because NO does not readily combine with itself to form a stable molecule, and also because it is a very reactive free radical, it has been recognized hereby that NO should be far more efficient than the superoxide free radical at whitening teeth. The superiority of the NO radical has also hereby been confirmed clinically.
Of particular importance for the formulation of a tooth whitening compositions is that NO− does not remain as a nitrogen oxide free radical moiety in aqueous solution. Instead, NO quickly yields nitrite (NO2—) and nitrate (NO3—) as end products in an aqueous environment. Therefore it is ultimately the FDA-approved nitrite or nitrate end product of Nitrogen radical-water chemistry that would be used as the predominant entity for the chromogen oxidizers in the aqueous whitening products described hereinbelow. Both the nitrate and nitrite end products possess an unpaired electron making it a reactive paramagnetic moiety which, as recognized here, is capable of rapidly interacting with organic stain molecules (chromogens) which contain carbon-carbon bonds filled with two electrons.
It may also be noted that in non-aqueous environments, it is possible that some NO− radicals may react rapidly with the superoxide radicals (typically found in tooth whitening chemistry), forming highly reactive peroxynitrite anions (ONOO—). However, the aqueous nature of the present invention precludes formation of these anions in significant amounts.
Another noteworthy outcome of nitrogen oxide whitening is that very small amounts of nitrosonium cations (NO+) and nitroxyl anions (NO−) will be formed in aqueous environments. At low concentrations these will not be biological systems, but because of their extremely high reactivity, it has been recognized hereby that they can interact with tooth surface chromogens in a more efficient manner than could either the hydroxyl or superoxide free radical.
Regarding their safety; Nitrite and Nitrate salts are typically supplied as white rhombic crystals. They are easily soluble in water and have strong gyroscopicity. These have typically been used in the food and fabric industries as bleaching agents, corrosion inhibitors, antitoxic and analytical agents. Daily exposure to Nitrites has been cautioned by the FDA (for example when used as a color fixative for meats); however it is also credited with significantly reducing the botulism risk in humans and is thus found commonly. It is also commonly used in pharmaceuticals; photographic and analytical reagents. Furthermore and even though safe, the compositions presented here are, according to conventional standards, not intended for daily use, but rather for a prescribed treatment time that in typical situations should perhaps not be repeated more than twice yearly (though more often may be practiced, as understood, and perhaps prescribed by a physician). Even further, the compositions hereof are not intended for consumption, but rather only intended for the topical applications described, as on the teeth in the primary examples.
Presented hereafter is background information on activating bleaching agents with light energy. Scientists have identified many kinds of ultraviolet (UV) photoactivators, which are capable of working in nature to reduce the color of chromophoric stains. These include: transition metal complexes, keto acids, riboflavin, pteridines, algal pigments, cyanocobalamine, thiamin, biotin and aromatic ketones. The pathways by which photo-bleaching can theoretically occur on tooth surfaces are of two types. First, if the absorption spectrum of the colored chromogen overlaps with the spectrum of incoming radiation, the substrate may undergo photoreaction directly, e.g., the notion of fading color with light. Secondly, and a likely more powerful explanation; UV energy may be absorbed by photo activators that then react with the tooth surface chromogens, resulting in an “indirect” photobleaching.
Indirect photobleaching is mediated by transient species (free radicals) that are rapidly consumed by subsequent reactions. For these mechanisms, the rate of reaction is determined by the quantity and type of chromogen, activator, free radicals and incoming UV radiation. Surface gradients involving any of these factors will lead to altered rates of photobleaching at the enamel/bleaching agent interface.
In nature, the major photochemical intermediate free radicals include singlet oxygen, O.; superoxide O2—; hydroperoxide HO2; and various other peroxy radicals, RO2. These have previously been described for the purpose of bleaching teeth.
Singlet oxygen free radicals, O. (the most common type of free radical liberated from hydrogen peroxide in the presence of light, heat or other activators), are formed primarily through energy transfer from the excited triplet states of dioxygen, 3O2. (as seen in the case of hydrogen peroxide), and wavelengths in the UV-A (315-400 nm) and UV-B (280-315 nm) spectra have been shown to be most effective in their formation. Quantum yields (the fraction or percentage of absorbed photons which give rise to products) range from 1-3% and generally decrease with increasing wavelength. Because the high concentrations of hydrogen peroxide or similar compounds are present in tooth bleaching preparations, its decay into water and O. is dominated by this pathway when UV light/activator systems are used in professional tooth bleaching formulas.
The exact mechanism of how these singlet oxygen free radicals come to be formed still remains unclear. Some researchers have suggested that O. is formed by direct electron transfer from the excited triplet states to O2. However, reduction of O2 by radicals or radical ions produced by intramolecular electron transfer reactions, H-atom abstractions and/or homolytic bond cleavages, is equally, if not more plausible. It is also known that transition metal complexes having one-electron reduction potentials falling between the O2/O2— and O2—/HO2O2 couples can rapidly catalyze O. free radical formation.
Even so, knowing that tooth bleaching formulations rely on the singlet oxygen O. free radical, the universe and the earth's natural environment takes a broader and more efficient approach to photobleaching. For example, it is known that in the oceans of the earth, there are other important photochemical radicals that work as intermediates in combination with bacterial hydrogen peroxide and are mostly responsible for photobleaching of coral reefs. These more efficient photobleaching reactions use NO− (nitrogen oxide) and NO3— & NO2— (nitrate/nitrite) radicals. Nitroxyl radical photobleaching chemistry (as described in depth by several researchers) may be initiated by UV from sunlight reacting with NO−, NO3— & NO2— (nitrate/nitrite) radicals.
Evidence for the photobleaching ability of nitrogen oxide radicals has been acquired by employing stable nitroxide radicals to trap the carbonate radicals, the immediate precursors to the reduced chromogen. Using a highly-sensitive fluorescence detection scheme combined with high performance liquid chromatography, a number of molecular fluorescent-tagged OH— and carbonate radicals have been detected in seawater and combined with high molecular weight chromophores. Note, just as important in nature are the highly reactive hydroxyl radicals, OH—, which again are much more reactive than singlet oxygen free radicals and are produced primarily through the photolysis of nitroxyl radicals. In this case, NO2— is known to react with UV light and peroxide formed by ocean bacteria and plankton to form the OH— radical. The OH— then reacts with an available carbon source producing carbonate radicals. The carbonate radical may then self-terminate in competition with its oxidation of organic chromogens into less colored molecules. The photolysis of Nitrate is also important. NO3— reacts with UV light and plankton H2O2 to generate OH— as well as NO2—. Subsequent reactions of NO2 can produce NO3— thereby coupling the dynamic cycles of NO2— and NO3— photobleaching.
Therefore the oxidation of the nitrogen oxide, nitrate and nitrite is very similar to photo-fenton reaction in which reduced metals such as Fe(II) react with H2O2 and UV light to produce a single OH— radical. However using nitrogen oxides in the oxidation process instead of hydrogen peroxide is much more powerful. This is because hydroxyl moieties are generated with less UV activation energy thus giving NO containing tooth whiteners the capability of producing more reduction in chromophoric tooth stain in a given period of time or for a given level of UV energy (the high quantum yield for this reaction is 98%).